MXPA06009315A - Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder - Google Patents

Abstract

The invention relates to the use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder.

Description

USE OF METRONIDAZOLE FOR THE TREATMENT OF A DISORDER OF CUTANEOUS VASCULARIZATION DESCRIPTION OF THE INVENTION The present invention relates to the treatment of cutaneous vascularization disorders, and more particularly to the treatment of cutaneous vascularization disorders in rosacea. The invention relates to providing new pharmaceutical compositions, more particularly dermatological, useful for the treatment of cutaneous vascularization disorders, and more particularly the treatment of cutaneous vascularization disorders in rosacea and comprising in the form of active agent the metronidazole Rosacea is a chronic and progressive common inflammatory dermatosis linked with vascular relaxation. It mainly affects the central part of the face and is characterized by the eruption of the face or heat flushes, facial erythema, papules, pustules and telangiectasia. In severe cases, particularly in man, the soft tissue of the nose can swell and produce a bulbous inflammation called rhinophy. In general, rosacea occurs between the ages of 25 and 70 years, and is much more common in people with fair complexions. REF. : 174523 It affects more particularly women, although this condition is generally more severe in men. Rosacea is chronic and persists over the years with periods of exacerbation and remission. Rosacea has been called originally "acne rosacea" because its papules (slight over-elevations of the skin) and its inflammatory pustules (scabs of pus) closely resemble those of acne vulgaris. In opposition to acne vulgaris, whose etiology is based on both an abnormal keratinization, an exacerbation of sebum production and a bacterial inflammation, the inflammation of rosacea is vascular in nature and poorly understood.- It results from this facial vascular anomaly , a permanent edema of the dermis that could accompany a colonization increased by Demodex folliculorum, a mite that is usually found in the follicles of the face. According to different studies, Demodex folliculorum would have an etiological role in rosacea (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425, Purcell et al., 1986, J Am Acad Dermatol, vol. 15, pages 1159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol.26, pages 590-593). It seems that Demodex folliculorum causes or aggravates inflammatory reactions, translating into papules and pustules, blocking the pilo-sebaceous follicles of the face (Roihu et al., 1998, J Cutan Pathol, vol.25, pages 550- 552). This parasite would also trigger a humoral immune response (Nunzi et al., 1980, Br J Dermatol, vol 103, pages 543-551, Manna et al., 1982, Br J Dermatol, vol 107, pages 203-208). The pathogenesis of rosacea is not well known. Numerous factors may be involved without strongly inducing this condition. For example, are psychological factors, gastrointestinal problems, environmental factors (exposure to the sun, temperature, humidity) and emotional (stress), food (alcohol, spices), hormonal, vascular, in addition to an infection by Helicobacter pylori.

Rosacea evolves in 4 states, but passing through all states is not mandatory: - state 1 of vascular relaxation (approximately 20 years). The patients have sudden growths of paroxysmal flushing of the face and neck, with a sensation of heat, but without systemic signs. After the crises, the skin of the face becomes normal. These "ruboraciones" are triggered by changes in temperature (sometimes leading to a thermophobia), the absorption of hot drinks or alcohol. - state 2 erythemato-telangiectatic (around 30 years). The malar zones are diffusely reddened. Dilated capillaries are observed that constitute the classic mud. Unlike state 1, the blush is permanent.

In addition, the cheeks may be intruded, the chin and the middle part of the forehead. state 3 of papulo-pustules (around 40 years old). On a background of erythema develop papules and pustules of a few millimeters in diameter, without associated comedones. This dermatosis can be very extensive, sometimes in the hairless part of the scalp in men, but it respects the contour of the mouth and eyes. Patients complain of sensitive skin, with subjective intolerance to most topics and fatty cosmetics. - condition 4 of the rhinophyma (around 50 years or later). This late phase affects mainly men, contrary to the other states. The nose increases in volume, diffusely red and dilated the follicular orifices. The skin becomes progressively thick. The minor forms of rosacea can be treated by active agents such as anti-seborrheic and anti-infective, for example benzoyl peroxide, retinoic acid. As for the more diffuse forms of affection, they correspond to a general antibiotic therapy by cyclins. However, these treatments have unpleasant side effects for the patient, such as irritation or intolerance. In addition, regarding the multi-factorial aspect of rosacea, there are very numerous therapies against this condition, but there is still the investigation of an effective treatment without risk for the patient. The works of the applicant allowed to highlight the interaction of metronidazole with the receptors chosen from the group comprising the béta-adrenergic receptors, the ATI receptor, the 5-HT2 receptor, the 5-HT5 receptor, the galanin receptor in the treatment of rosacea. Beta-adrenergic receptors are involved in the regulation of various physiological functions, such as metabolic activity, cardiac activity, respiration, central nervous system activity, blood pressure and vascular tone. The 5-HT2 receptors, the 5-HT5 receptors belong to the family of serotonin (5-HT) receptors. The group of 5-HT receptors are coupled to G proteins, except for 5HT3, which is an ion channel. The activation of 5-HT2 receptors stimulates the activity of phospholipase C. The transduction system of 5-HT5 receptors is positively associated with adenylate cyclase. The AT1 receptor is involved in the regulation of vasoconstriction by angiotensin II. In man, angiotensin II increases the tone of the subcutaneous arteries.

Galanin is a peptide of 29 amino acids present in the central nervous system. According to some works, The galanin could play a role in the modulation of the cutaneous vascular reaction and inflammation (Pincelli, 1990, Br J dermatol, vol 122, pages 745-750). Metronidazole, or (methyl-2-nitro-5-imidazolyl) -2-ethanol, is known in the prior art for its antibacterial, antiparasitic and antiprotozoal properties. It exerts a selective toxicity with respect to anaerobic microorganisms as well as hypoxic cells. At the level of the latter, metronidazole is reduced in derivatives, capable of altering the DNA structure of these cells. The Applicant's work allowed to highlight the involvement of the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor in cutaneous vascularization disorders. The Applicant's work allowed to highlight the interesting properties of metronidazole on cutaneous vascularization disorders and more particularly on the disorders of cutaneous vascularization in rosacea. It has been surprisingly found that the use of metronidazole would, as a consequence, have an interaction with the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. More particularly, it was found that the use of Metronidazole inhibits the binding of natural ligands to these receptors. As indicated above, the invention aims to offer a new method of treating a cutaneous vascular disorder consisting of administering to a patient, affected by cutaneous vascularization disorders, an effective amount of metronidazole, in which the metronidazole is capable of interact with at least one receptor selected from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. Accordingly, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition, intended for the treatment of a disorder of cutaneous vascularization.

More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least one receptor chosen from the group comprising the beta-adrenergic receptors, the ATl receptor , the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended to treat a vascular disorder cutaneous, which involves at least two receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended to treat a cutaneous vascular disorder, involving at least three receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the receptor 5-HT2, the 5-HT5 receptor and the galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended to treat a cutaneous vascular disorder, involving at least four receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the receptor 5-HT2, the 5-HT5 receptor and the galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended to treat a cutaneous vascular disorder, involving at least five receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the receptor 5-HT2, the 5-HT5 receptor and the galanin receptor.

More particularly, the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended to treat a cutaneous vascular disorder, the cutaneous vascular disorder being a component of rosacea and the metronidazole being capable of interacting with it. less a receptor selected from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, wherein metronidazole is capable of interacting with at least two receptors chosen from the group comprising beta-adrenergic receptors, ATl receptor, 5-HT2 receptor, 5-HT5 receptor and galanin receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, wherein the metronidazole is capable of interacting with at least three receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, 5-HT2 receptor, 5-HT5 receptor and galanin receptor. The invention also relates to the use of metronidazole for the preparation of a composition Pharmaceutical as defined above, wherein the metronidazole is capable of interacting with at least four receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the receptor of galanin. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition defined above, wherein the metronidazole is capable of interacting with at least five receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition in which metronidazole inhibits the binding of at least one natural ligand to its receptor, the receptor of the group comprising the beta-receptors being chosen. adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. The objective composition of the present invention is a dermatological composition, for topical administration on the skin. By treatment of cutaneous vascularization disorders, it is understood according to the present invention, the treatment and / or prevention of such disorder.

By treatment of rosacea, it is understood according to the invention, the treatment and / or prevention of rosacea, with one or more of the conditions described above. According to a first embodiment of the invention, the composition is intended for the treatment of the first state of rosacea. According to a second embodiment of the invention, the composition is intended for the treatment of the second state of rosacea. According to a third embodiment of the invention, the composition is intended for the treatment of the third state of rosacea. According to a fourth embodiment of the invention, the composition is intended for the treatment of the fourth state of rosacea. According to a preferred embodiment, the composition contains 0.0001 to 20% by weight of metronidazole, preferably 0. 1 to 2% and more preferably of the order of 0.75 to 1% of metronidazole expressed by weight relative to the total weight of the composition. Of course, the present invention relates, in addition to the use of metronidazole, to the use of derivatives thereof. Derivatives of compounds that are distinguished from metronidazole are understood as substitution, addition or deletion of one or several chemical groups and that present sensibly the same activity. -. Advantageously, the compositions of the invention comprise in addition to metronidazole, at least one other therapeutic agent capable of increasing the effectiveness of the treatment. As non-limiting examples of these agents, there may be mentioned antibiotics, antibacterial, antiviral, antiparasitic, antifungal, anesthetic, analgesic, antiallergic, retinoid, anti-free radical, anti-pruritic, keratolytic, antiseborrhoeic, anti -histamines, sulfides, immunosuppressive or antiproliferative products. The compositions of the invention may further comprise any additive commonly used in the pharmaceutical, dermatological domain, compatible with metronidazole. Mention may be made in particular of sequestrants, antioxidants, sunscreens, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, colorants, base or customary, mineral or organic acids, perfumes, essential oils, cosmetic actives, moisturizers. , vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, thickening agents and skin protectants such as allantoin, pro-penetrants, gelling agents. Of course, the experienced will know how to choose this or these optional complementary compounds, and / or their amount, in such a way that the advantageous properties of the composition according to the invention are not, or are not substantially altered. These additives may be present in the composition in a proportion of 0 to 20% by weight relative to the total weight of the composition. Examples which may be mentioned are sequestering agents, ethylenediamine tetraacetic acid (EDTA), as well as their derivatives or their salts, dihydroxyethylglycine, citric acid, tartaric acid or their mixtures. Mention may be made, as examples of preservatives, of benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens or their mixtures. Examples of wetting agents are glycerin and sorbitol. The compositions of the invention may contain one or more propenetrating agents in preferential concentrations ranging from 0 to 20% and more preferably ranging from 0.6 to 3% by weight, based on the total weight of the composition. Among the propenetrating agents, compounds such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol, are preferably used without this list being limiting.

Advantageously, the compositions according to the invention can also contain one or more surfactants in concentrations preferably ranging from 0 to 10% and more preferably ranging from 0.1 to 2%. The compositions of the present invention can be presented under all galenic forms normally used for a topical application, in particular in the form of aqueous, hydroalcoholic or oily solutions, of lotion-type dispersions, of aqueous gels, anhydrides or lipophilic, emulsions of liquid or semi-liquid consistency of the milky type, obtained by dispersing a fatty phase in a phase aqueous _ (H / E) or vice versa (E / H) or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, gel or ointment type or even of micro-emulsions, micro-capsules, micro-particles or of vesicular dispersions of ionic and / or nonionic type. Preferably, the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax or water that is instantaneously emulsified, in which is added metronidazole, dissolved in a small amount of oil, such as almond oil. The ointments can be formulated by mixing a solution of metronidazole in an oil, such as almond oil in hot paraffin, then allowing the mixture to cool. As examples of the compositions in accordance with The invention may include those comprising an active phase containing (expressed as a percentage by weight): 0 to 90%, preferably 5 to 25%, particularly 10 to 20%, of water; - 0 to 10%, preferably 0 to 2%, particularly 0 to 0.5%, of surfactant; - 0 to 20%, preferably 0 to 10%, particularly 2 to 5%, of propenetrant; 0.0001 to 20%, preferably 0.1 to 2%, of metronidazole; and an aqueous phase comprising a gelling agent and water. The aqueous phase of a composition according to "invention that is presented in the form of an emulsion may comprise water, a floral water, such as cranberry water or a thermal water or natural mineral, for example chosen from Vittel water, Vichy bath waters , the water of Uriage, the water of the Roche Posay, the water of the Bourboule, the water of Enghien-les-Bains, the water of Saint Gervais-les-Bains, the water of Neris-les-Bains, the water of Allevard-les-Bains, the water of Digne, the water of Maiziéres, the water of Neyrac-les-Bains, the water of Lons-le-Saunier, the Eaux Bonnes (good waters), the water of Rochefort, the water of Saint Christau, the water of Fumades and the water of Tercis-les-bains, the water of Avene (oats) or the water of Aix les Bains.This watery phase can be presented in an amount comprised between 10 and 90% by weight relative to the total weight of the composition, preferably comprised between 20 and 80% by weight. By way of non-limiting examples, mention may be made of gelling agents of the polyacrylamide family, such as the mixture of the copolymer sodium acryloyldimethyltaurate / isohexadecane / polysorbate 80 sold under the name Simulgel 600 by the company Seppic, the mixture of polyacrylamide / isoparaffin C13-14 / laureth-7 as, for example, sold under the name of Sepigel 305 by the company Seppic, the family of acrylic polymers coupled to hydrophobic chains, such as the PEG-150 / decyl / SMDI copolymer sold under the name Aculyn 44 (polycondensate comprising, at least as elements, a polyethylene glycol with 150 to 180 moles of ethylene oxide, of decyl alcohol and methylene bis (4-cyclohexyl isocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%), the family of modified starches such as modified potato starch sold under the name of Structure Solanace or their mixtures . Preferred gelling agents come from the family of polyacrylamides such as Simulgel 600 or Sepigel 305 or their mixtures. The gelling agent as described above can be used at the preferred concentrations ranging from 0.1 to 15% and, more preferably, ranging from 0.5 to 5%. The gels can be preferably prepared by dispersing or dissolving the metronidazole in an appropriate ratio, in a carbomer, poloxamer or cellulose type gel. Other advantages and features of the invention will appear from the examples below with respect to the inventive activity of metronidazole.

Example 1 - Activity of metronidazole. 1) Protocol: The test for binding to the beta-1 and beta-2 adrenergic receptors was carried out following the protocol described by Smith and Teilier 1999, Cardiovasc Drug Ther, vol. 13, pages 123-126. The ATl receptor binding test was performed following the method described by Bergs et al., 1992, Biochem Biophys Res Comm, vol. 183, pages 989-995. The 5-HT5A receptor binding test was performed following the method described by Ress et al., 1994, FEBS Lett, vol. 355, pages 242-246. The 5-HT2A 'receptor binding test was performed following the method described by Bonhauss et al., 1995, Brit J Pharmacol, vol. 1155, pages 622-628. The galanin receptor binding test was performed following the method described by Sullivan et al., 1997, Biochem Biophys Res Comm, vol. 233, pages 823-828. 2) Experimental conditions: The binding of metronidazole on each receptor was determined by the competition experiences. The receptor, recombinant human protein, was incubated according to the times indicated in Table 1 below, with a single concentration of labeled specific ligand, in the presence of 10 μM metronidazole. The bound radioactivity was measured by scintillation counting.

Table 1 3) Expression analysis of the results: The specific binding of the ligand to the receptor is defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. The results are expressed in percentage of controlled specific binding and percentage of inhibition of the specific controlled binding obtained in the presence of metronidazole (Table 2).

Table 2 In this way, metronidazole interacts and induces binding to the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (17)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a disorder of cutaneous vascularization.
2. 2. Use according to claim 1, wherein the cutaneous vascular disorder involves at least one receptor selected from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the receptor. of the galanin.
3. 3. Use according to claim 1 or 2, wherein the cutaneous vascular disorder involves at least two receptors chosen from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the receptor of galanin.
4. 4. Use according to any of claims 1 to 3, wherein the cutaneous vascular disorder involves at least three receptors chosen from the group comprising the beta-adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5- receptor HT5 and the galanin receptor.
5. 5. Use according to any of claims 1 to 4, wherein the vascular disorder cutaneous - involves at least four receptors chosen from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor.
6. 6. Use of the metronidazole according to any of claims 1 to 5, wherein the cutaneous vascular disorder involves at least five receptors chosen from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the receptor 5-HT5 and the galanin receptor.
7. 7. Use according to claim 1, wherein the vascular disorder is a component of rosacea and wherein the metronidazole is capable of interacting with at least one receptor selected from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor.
8. 8. Use according to any of claims 1 to 7, wherein the metronidazole inhibits the binding of at least one natural ligand to its receptor, the receptor being chosen from the group comprising the beta adrenergic receptors, the ATl receptor, the 5-HT2 receptor, the 5-HT5 receptor and the galanin receptor.
9. 9. Use according to any of claims 1 to 8, wherein the pharmaceutical composition It is a dermatological composition for topical application.
10. 10. Use according to any of claims 1 to 9, wherein the composition is intended for the treatment of at least one state of rosacea.
11. 11. Use according to any of claims 1 to 10, wherein the composition is intended for the treatment of the first state of rosacea.
12. 12. Use according to any of claims 1 to 11, wherein the composition is intended for the treatment of the second state of rosacea.
13. 13. Use according to any of claims 1 to 12, wherein the composition is intended for the treatment of the third state of rosacea.
14. 14. Use according to any of claims 1 to 13, wherein the composition is intended for the treatment of the fourth state of rosacea.
15. 15. Use according to any of claims 1 to 14, wherein the composition contains from 0.0001 to 20% by weight, preferably from 0.1 to 2% and more preferably in the order of 0.75 to 1% by weight of metronidazole.
16. 16. Use according to any of claims 1 to 15, wherein the composition further contains an active agent selected from the group of antibiotics, antibacterials, antivirals, antiparasitic, antifungal, anesthetic, analgesic, antiallergic, retinoid, anti-free radical, anti-pruritic, keratolytic, anti-seborrheic, antihistamines, sulfides, immunosuppressive or antiproliferative products.
17. 17. Use according to any of claims 1 to 16, wherein the composition contains an additive selected from the group of sequestrants, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, bases or usual acids, minerals organic, perfumes, essential oils, cosmetic actives, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, thickeners and skin protection agents, pro-penetrants, gelling agents or a mixture of these.